The protective structures of the anterior surface of the eye include the eyelids, conjunctiva, and the cornea. The posterior surfaces of the lids are covered with a mucous membrane and the palpebral conjunctiva which reflects onto the eye to become the bulbar conjunctiva. The bulbar conjunctival epithelium is continuous with the corneal epithelium which accounts for about 10% of the anterior surface of the eye and is where most of the stationary refraction occurs.
The corneal epithelium is 4-5 cells thick and the superficial cells contain many microvilli. These aid in maintaining the moisture of the epithelial surface by promoting the adhesion of the tear film to the surface. This film lubricates the anterior surface of the eye to decrease the frictional forces arising from the persistent blinking movements of the eyelids, foreign particles on the surface of the eye, and the rotational movements of the eyeball. The tear film also transfers oxygen from ambient air to the cornea.
The anterior surface of the eye is vulnerable to damages inflicted by various causes including mechanical abrasion of the cornea; contact lens wearing; spontaneous peeling of the epithelium; damaged epithelium and stroma following photo-refractive keratectomy; chemical burns; over exposure to ultraviolet light including sunlight; systemic diseases such as Sjogren syndrome, Steven-Johnson syndrome, Cicatricial pemphigoid syndrome; chronic edema of cornea with recurrent erosion of epithelium; impaired tear film formation, and conditions following damage of epithelia due to radial keratotomy.
Aging often causes disorders resulting from slow regeneration of the epithelium. The impaired regeneration and abnormality of the cells causes thinning of the epithelial layer and its impaired adherence to the basal lamina thus decreasing the ability of the cornea to retain the tear film leading to further epithelial damage.
Following injury to the corneal epithelium, nearby cells retract slightly, round up and begin an ameboid migration from the basal layer across the exposed basement membrane to cover the defect with a new monolayer of cells. These cells then take on the characteristics of a new basal layer and undergo mitosis to gradually fill in the defect with the full complement of four to five layers of cells. Present treatment for corneal wounds involves applying eye drops to the surface in order to protect the delicate healing process from erosion due to blinking and the other sources of friction. There are no currently used medicaments that promote the healing process itself. Attempts to administer fibronectin in order to promote healing of persistent defects of the corneal epithelium failed (Fukuda et al., Am J. Ophthalmol., 119(3):281-287, (1995)).
It would have been highly desirable to provide an ophthalmic composition capable of protecting the corneal epithelium and enhancing its healing and regeneration.
The rate of cell proliferation in many cell types has been correlated with the rate of cholesterol synthesis, and more specifically with the biosynthesis of various intermediates in the cholesterol biosynthesis pathway and their by-products such as farnesylated proteins and others. Thus, inhibition of an early enzyme in the biosynthesis of cholesterol inhibits cell growth in cultured fibroblasts (McGuire et al., J. Biol. Chem., 268:22227-22230, (1993)). Factors which cause cholesterol efflux from cells (e.g. high density lipoproteins, HDL) alleviate the negative feedback inhibition of cholesterol synthesis and enhance growth of MDCK cells in vitro (Gospodarowicz et al., J. Cell. Physiol., 117:76-90, (1983)).
The cornea is an avascular organ obtaining nutrition from the vasculature of the limbus by diffusion. At the outer surface of the cornea, the epithelium is essentially isolated from the plasma's large complexes such as HDL which hardly diffuse through the cornea. Thus, HDL which performs the “reverse cholesterol transport” from peripheral organs to the liver (Glomset, J. A., J. Lipid Res., 9:155-167, 1968) is unable to perform this task in the corneal epithelium.